Relation between lobular neoplasia and calcification
An important question in the management of lobular neoplasia on core biopsy is the relationship between lobular neoplasia and calcification. Lobular neoplasia is not typically associated with any specific clinical abnormality, and there are no characteristic macroscopic features. Early papers suggested that classical lobular neoplasia does not have any diagnostic mammographic features [
4]. In the past, surgical biopsies containing lobular neoplasia were frequently performed for mammographic calcification, but pathologically, the calcification was mostly associated with fibrocystic change and identified within the lobular neoplasia in about 20% [
4,
11,
24,
55]. Calcification is associated with the lobular neoplasia in between 8% and 53% of core biopsies containing classical lobular neoplasia in different studies [
1,
3,
14,
20,
41]. Benign calcification is frequently seen close to invasive carcinomas in surgical specimens [
52]. It is well recognised that malignancy may be an incidental discovery on a biopsy for calcification that is associated only with benign disease [
49].
The present study confirms the association between lobular neoplasia and columnar cell change [
8,
41]. In older studies, the majority of surgical biopsies containing lobular neoplasia were performed for fibrocystic change [
30]. In the present study, calcification was associated with lobular neoplasia in 15% of core biopsies, but commonly was also seen in fibrocystic change as well. Calcification was associated with columnar cell change in 32% of cores with lobular neoplasia. The association of calcification with columnar cell change is well recognised [
27]. Our results support the view that, in biopsies containing lobular neoplasia, most of the calcification is associated with fibrocystic change, particularly columnar cell change. Importantly, the lobular neoplasia is incidental to the calcification in the majority of biopsies.
A recent study of collagenous spherulosis found that 15 of 59 patients had associated LCIS [
48]. In contrast, only one of the patients in the present study with lobular neoplasia had associated collagenous spherulosis.
Relationship between simple classical lobular neoplasia and carcinoma
In this study, 44 women with simple classical lobular neoplasia on core biopsy had surgical excision or follow-up of at least 2 years. Twenty-five women had immediate surgical excision, which showed invasive carcinoma, DCIS or pleomorphic LCIS in nine (36%). In the majority, the core biopsy was judged to have missed the clinical/radiological lesion. This emphasises the importance of clinico-pathological review and further investigation of any discordance. Most of the missed lesions occurred in the early part of the study, suggesting that the accuracy of radiological localisation of core biopsies may have improved later in the series. A smaller number of carcinomas occurred after lobular neoplasia on core biopsy apparently incidental to the clinical or radiological lesion. This raises the question of whether excision biopsy should be considered after all core biopsy diagnoses of lobular neoplasia. The frequency of malignancy if the patients with radiological–pathological discordance are excluded is 11% (2/18).
Four of 19 patients with at least 2 years follow-up developed carcinoma at the site of the core biopsy. In one, the carcinoma was mammographically occult, although it was clinically palpable, in one the original mammogram was dense and two women had calcification apparently adequately sampled by the core biopsy. Definite comment cannot be made, but the clinical histories suggest that it is possible that the carcinoma may have been identified earlier in some of these patients if they had had an immediate surgical biopsy. If these women are added to those without radiological–pathological discordance in the above paragraph, the frequency of malignancy is 16% (6/37).
Previous published studies of simple lobular neoplasia on core biopsy were reviewed [
1‐
3,
6,
9,
10,
12,
14,
16‐
18,
20,
21,
23,
25,
26,
31,
33,
36,
37,
39,
41‐
43,
46,
47,
51,
54,
58,
59]. The data in most studies are not representative. Probably the major bias is that only about half of the lesions had a surgical biopsy and it is not clear how patients were selected for excision biopsy. Furthermore, most studies only report image-guided or stereotactic biopsies. A surgical biopsy was performed in 561 patients with a core biopsy diagnosis of lobular neoplasia with invasive carcinoma found in 50 or 49 and DCIS in 32 or 33 (82 [15%] in total). It is ‘impossible to know if some of the reported cases are those in which the targeted lesion has been missed and re-excision was done for failure to successfully sample the target’ [
15]. In reviewing the previous studies, we have assumed that sampling was adequate for core biopsy performed for calcification if calcification was present in the core biopsy. Of those 52 malignancies with details available, 25 (48%) had a radiological–pathological discordance (missed mass in 22 and missed calcification in 3), and 27 had apparently adequately sampled calcification.
One hundred four patients who did not have immediate surgical excision had reported follow-up. The only four patients (4%) with invasive carcinoma or DCIS on follow-up at the site of core biopsy are the four patients described in the present study. The absence of subsequent malignancy in other studies is very surprising given that lobular neoplasia is a well-established risk factor for later carcinoma. Nevertheless, the low rate suggests that the chance of invasive carcinoma or DCIS is lower in those not having immediate surgical excision.
It is difficult to estimate the chance of finding invasive carcinoma or DCIS if all patients had an excision biopsy. The 15% rate found in the subset of patients who had immediate excision biopsy is probably an overestimate. If the cases with radiological–pathological discordance are excluded, the risk is probably about half of this, approximately 8%. If one assumes that half of the patients who did not have an immediate excision did not have invasive carcinoma or DCIS at the core site, this gives an estimate of about 4%. This represents an estimate of the lower limit of risk.
Some studies suggest that the risk of finding invasive carcinoma or DCIS is a little higher if the core biopsy shows LCIS rather than ALH [
13]. In view of the subjectivity of this distinction on core biopsy, it is probably of limited use in routine practice.
It is clearly appropriate to investigate patients with simple classical lobular neoplasia on core biopsy that does not explain the clinical or radiological abnormality. If a definitive diagnosis cannot be made with further core biopsy, then an excision biopsy is indicated.
The management of simple classical lobular neoplasia on core biopsy with no radiological–pathological discordance is less straightforward. As discussed above, the literature suggests that the risk of malignancy is in the range of 4% to 8%. This risk is comparable to that associated with radial scar or papillary lesion with no epithelial atypia [
7,
34,
35,
40,
53]. Both radial scars and papillary lesions are excised in many centres according to current guidance [
19]. The major difference with lobular neoplasia, however, is that both are usually clearly defined lesions on radiological examination and therefore easy to excise.
There is a need for prospective studies with surgical excision of all lesions so that an unbiased assessment of the risk of simple classical lobular neoplasia on core biopsy can be made. Careful radiology–pathology correlation is essential. It may be possible to stratify the risk within this group using clinical, radiological or pathological features.
Pleomorphic LCIS
In the present study, both cores with pleomorphic LCIS had associated calcification. In contrast to the controversial nature of the association between calcification and classical LCIS, the literature suggests that there is a clear relationship between calcification and pleomorphic LCIS [
29,
50]. There are limited data on the significance of pleomorphic LCIS on core biopsy. One of the two patients in the present study had DCIS in the excision specimen. Three of the six patients described in the literature [
5,
20,
37] had invasive carcinoma on excision, but radiology showed a density in one and an architectural distortion in another. Although the follow-up data are limited, we believe that, until there is further evidence, it is prudent to recommend that pleomorphic LCIS is managed as DCIS because of the morphological similarity of pleomorphic LCIS to high-grade DCIS. The present study may underestimate the frequency of pleomorphic LCIS, as E-cadherin immunohistochemistry was infrequently performed early in the study period and some cases may have been diagnosed as high-grade DCIS.
Some lobular neoplasia shows features overlapping with DCIS and is difficult to classify even with E-cadherin immunohistochemistry [
32,
38]. Lobular neoplasia with comedo necrosis, but without marked nuclear pleomorphism, has recently been described [
22]. The clinical significance of these rare clinico-pathological scenarios is uncertain. Until there is more evidence, it would be prudent to recommend surgical biopsy of such lesions because of the overlap of features with DCIS. Mass forming lobular neoplasia can occur rarely [
56], but is an example of clinico-pathological discordance, so surgical biopsy is prudent.
In conclusion, we recommend excision after a core biopsy diagnosis of lobular neoplasia in the following circumstances:
1.
Discordance of clinical or radiological findings with the pathological changes (this includes mass-forming lobular neoplasia)
2.
Lobular neoplasia with atypical histological features including pleomorphic LCIS, lobular neoplasia with necrosis, and when it is not possible to exclude DCIS despite E-cadherin immunohistochemistry
3.
If there is an associated risk lesion, such as atypical intraductal epithelial proliferation, radial scar or papillary lesion.
We suggest that further studies are needed to guide the management of simple classical lobular neoplasia, as the data on the risk of associated carcinoma remain unclear in this group of patients.